Anti-inflammatory agents

ABSTRACT

THE TREATMENT OF INFLAMMATION, PAIN AND FEVER UTILIZING COMPOSITIONS CONTAINING ALKYL SUBSTITUTED PYRIDONES, THIOPYRIDONES AND PYRIDINES.

United States Patent 3,655,897 ANTI-INFLAMMATORY AGENTS Bruce E. Witzel,Westfield, N.J., assignor to Merck & Co., Inc., Rahway, NJ.

No Drawing. Continuation-impart of application Ser. No. 879,925, Nov.25, 1969. This application Jan. 25, 1971, Ser. No. 109,707

Int. Cl. A6Ik 27/00 US. Cl. 424-263 30 Claims ABSTRACT OF THE DISCLOSUREThe treatment of inflammation, pain and fever utilizing compositionscontaining alkyl substituted pyridones, thiopyridones and pyridines.

This application is a continuation-in-part of US. application Ser. No.879,925, filed Nov. 25, 1969.

This invention relates to a method of treating infiam-.

mation in its varying manifestations, utilizing novel antiinflammatorycompositions containing alkyl pyridones and pyridines. In addition,these novel compositions exhibit potent analgesic and antipyreticactivity and, therefore, this invention also relates to analgesic andantipyretic methods and compositions. More particularly, this inventionis concerned with compositions containing alkyl pyridones and pyridinesfor use in the treatment of inflammation and associated pain and fever.Furthermore, this invention is directed to analgesic and antipyreticmethods for the relief and treatment of pain and fever notsymptomatically related to an inflammatory indication and compositionsutilized therefore.

The alkyl pyridones and pyridines employed in the treatment of acondition symptomatically evidenced by pain, fever and inflammation,either as an essential or concommitant phenomena of the condition arerepresented by the following formulas:

a a Ra 2 R1 and R4 R;

X Z X N N R4 L X in which X is O, S; R R R and R is hydrogen, alkyl(preferably lower alkyl such as methyl, ethyl, propyl, butyl and pentyl,etc.), cycloalkyl (preferably cycloloweralkyl such as cycolpropyl,cyclobutyl, cyclopentyl, etc.) with the proviso that at least one of theRs is alkyl or cycloalkyl; Z is H, alkyl (preferably lower alkyl such asethyl and propyl); aryl such as naphthyl, and phenyl includingsubstituted phenyl such as tolyl, halophenyl, hydroxyphenyl, anisyl,etc., acyl such as formyl, acetyl, propionyl, butyryl, etc. and benzoyl;L may be hydrogen; alkyl (preferably loweralkyl such as methyl, ethyl,propyl, etc.); alkenyl (preferably lower alkenyl such as vinyl, allyl,methallyl, etc.); alkynyl (preferably lower alkynyl such as ethynyl,methylbutynyl, propynyl, etc.); aralkyl (preferably arloweralkyl such asbenzyl and substituted benzyl, phenethyl, phenylhexyl, etc.); aryl(preferably phenyl) or substituted phenyl (such as tolyl, halophenyl,hydroxyphenyl, anisyl, etc.); hydroxyalkyl (preferably hydroxyloweralkylsuch as hydroxyethyl, hydroxypropyl, etc.); amino, dialkylamino(preferably diloweralkylamino, methylethylamino, etc.);dialkylaminoalkyl (preferably diloweralkylamino loweralkyl such asdiethylaminoethyl, etc.); alkylaminoalkyl (preferablyloweralkylaminoloweralkyl); alkylamino (preferably loweralkylamino suchas methylamino, ethylamino, etc.); carboxyalkyl (preferablycarboxyloweralkyl such as carboxymethyl, carboxyethyl, carboxypropyl,etc.); haloalkyl (preferably haloloweralkyl such as trifluoromethyl,etc.); hydroxy; alkoxy; alkylamidoalkyl (preferably loweralkylamidoloweralkyl such as acetamidoethyl, etc.); alkoxyalkyl;N-alkanoylalkylaminoalkyl such as N-acetylmethylaminoethyl; N-alkyl-N-alkyl-aminoalkyl such as N-ethyl-N-methylaminopropyl; aralkenyl(preferably arloweralkenyl such as styryl, phenylpropylenyl,phenylbutylenyl, etc.); heterocyclic such as furyl, tetrahydropyranyl,thienyl, thiazolyl, imidazolyl, oxazolyl, pyridyl and substitutedderivatives thereof, etc.

In its preferred aspects this invention relates to the class of chemicalcompounds of Formula I wherein L is hydrogen,lalkyl or aryl, X=oxygenand at least one R is lower alky Representative of the preferredcompounds of the invention include the following:

4-methyl-2 1H] -pyridone 3-methyl-2[ 1H] -pyridone S-methyl-Z 1H]-pyridone 4-ethyl-2[ 1H] -pyridone 4-t-butyl-2[ 1H] -pyridone5-t-butyl-2 1H] -pyridone 6-methyl-2 1H] -pyridone 3,4-dimethyl-2 1H]-Pyridone 6-i-buty1-2[ 1H] -pyridone 4,5-dimethyl2[ 1H] -pyridone5-t-butyl-4-methyl-2 1H] -pyridone 5-n-butyl-2[ 1H] -pyridone5-i-propyl-2 1H] -pyridone S-cyclohexyl-Z 1H] -pyridone G-butyl-5-methyl-2[ 1H] -pyridone 6-pentyl-2 1H] -pyridone S-butyl- 6-methyl-21H] -pyridone 3-ethyl-4-methyl-2 1H] -Py idone 5-ethyl-4-methyl-2[ 1H]-pyridone 5-i-propyl-6-methyl-2[ 1H] -pyridone Other illustrative alkylpyridines and pyridones Within the scope of the invention include:1-methyl-4-butyl-2 1H] -pyridone 4-t-butyl-2[ 1H] -thiopyridone 5-cyclopentyl-2 1H] -thiopyridone 5-ethyl-4-methyl-2 1H] -thiopyridone1-phenyl-4-t-butyl-2 1H] -pyridone 4,5 ,6-trimethyl-2 1H] -pyridone4-ethyl-5-cyclopropyl-2 1H] -pyridone 1-allyl- 6-methyl-2[ 1H] -pyridone1-ethoxy-4-t-butyl-2[ 1H] -thiopyridone 3-ethyl-1-hydroxy-2 1H]-pyridone 1-amin0-4-cyclohexyl-2 1H] -pyridone1-dimethylamino-4-t-butyl-2 1H] -pyridone1-aminoethyl-6-butyl-5-methyl-2 1H] pyridone l-ethoxymethyl-S,4-dimethyl-2[ 1H] -pyridone 4-ethyll-propylaminomethyl-Z 1H] -pyridoneare indicated for a wide variety of conditions where one or more of thesymptoms of inflammation, fever and pain are manifested. Included withinthis category are diseases such as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever. As indicatedabove the compounds utilized in the practice of the invention alsopossess a useful degree of analgesic and antipyretic activity.

For these purposes the compounds of the invention may be administeredorally, topically, parenterally, by inhalation spray or rectally indosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrasternal injection or infusion techniques. Inaddition to the treatment of warm-blooded animals such as mice, rats,horses, dogs, cats, etc., the compounds of the invention are elfectivein the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs. Compositions infororal use may be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide a pharmaceutically elegant and palatablepreparation. Tablets contain the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients which are suitable formanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example maize starch, or alginic acid; binding agents, for examplestarch, gelatine or acacia, and lubricating agents, for examplemagnesium stearate, stearic acid or tale. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate above or with a wax may beemployed.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules wherein the active ingredient is mixed withwater or an oil medium, for example arachis oil, peanut.

oil, liquid paraflin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturallyoccurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene' stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol mono-oleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyoxyethylene sorbitanmono-oleate. The said aqueous suspensions may also contain one or morepreservatives, for example ethyl or n-propyl p-hydroxy benzoate, one ormore coloring agents, one or more flavoring agents and one or moresweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil .orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaflin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of anantioxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agents and suspending agents areexemplified by those already mentioned above. Additional excipients, forexample sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents. Thepharmaceutical compositions may be in the form of a sterile injectablepreparation, for example as a sterile injectable aqueous or ole'agenoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringers solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic monoor diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectibles.

The compounds of this invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensionsetc. containing the anti-inflammatory agents are employed.

Dosage levels of the order of 20 mg. to 7 grams per day are useful inthe treatment of the above indicated conditions. For example,inflammation is effectively treated and anti-pyretic and analgesicactivity manifested by the administration from about .3 to milligrams ofthe compound per kilogram of body Weight per day. Advantageously fromabout 2 mg. to about 50 mg. per kilogram of body weight and especiallyfrom about 4 mg. to about 20 mg./kg. per daily dosage produce highlyeffective results.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example aformulation intended for the oral administration of humans may containfrom mg. to 5 grams of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 25 mg. to about 500 mg. of activeingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

The following are illustrative of the techniques that may be employed inthe preparation of pharmaceutical formulations to be utilized in thepractice of the invention:

EXAMPLE 1 A mixture of 250 parts of 4-t-butyl-2[1H]-pyridone and 25parts of lactose is granulated with suitable Water, and to this is added100 parts of maize starch. The mass is passed through a 16 mesh screen.The granules are dried at a temperature below 60 C. The dry granules arepassed through a 16 mesh screen, and mixed with 3.8 parts of magnesiumstearate. They are then compressed into tablets suitable for oraladministration.

The 4-t-butyl-2[.lH]-pyridone used in the foregoing example may bereplaced by 25, 100, 250, or 500 parts of other pyridones of thisinvention to produce tablets suitable for oral administration as ananti-inflammatory, antipyretic and/or analgesic according to the methodof this invention.

EXAMPLE 2 A mixture of 50 parts of 4-methyl-2[lH]-pyridone, 3 parts ofthe calcium salt of lignin sulphonic acid, and 237 parts of water isball-milled until the size of substantially all of the particles of4-methyl-2[1H]-pyridone is less than microns. The suspension is dilutedwith a solution containing 3 parts of sodium carboxymethylcellulose and0.9 part of the butyl ester of p-hydroxybenzoic acid in 300 parts ofwater. There is thus obtained an aqueous suspension suitable for oraladministration for therapetutic purposes.

EXAMPLE 3 A mixture of 250 parts of 5-methyl-2[lH]-pyridone, 200 partsof maize starch and 30 parts of alginic acid is mixed with a suflicientquantity of a 10% aqueous paste of maize starch, and granulated. Thegranules are dried in a current of warm air and the dry granules arethen passed through a 16-mesh screen, mixed with 6 parts of magnesiumstearate and compressed into tablet form to obtain tablets suitable fororal administration.

EXAMPLE 4 A mixture of 500 parts 4-ethyl-2[1H]-pyridone, 60 parts maizestarch and 20 parts of gum acacia i's granulated with a sufiicientquantity of water. The mass is passed through a 12-mesh screen and thegranules are dried in a current of warm air. The dry granules are passedthrough a 16-mesh screen, mixed with 5 parts of magnesium stearate andcompressed into tablet form suitable for oral administration.

EXAMPLE 5 (1) Tablets-10,000 scored tablets for oral use, eachcontaining 500 mg. of pyridone, are prepared from the followingingredients:

Gm. 3,4-dimethyl-2[lH]-pylidone 5000 Starch, U.S.P. 350 Talc, U.S.P. 250Calcium stearate a- 35 The powdered pyridone is granulated with a 4%w./v. aqueous solution of methylcellulose U.S.P. (1500 cps.). To thedried granules is added a mixture of the remainder of the ingredientsand the final mixture compressed into tablets of proper weight.

(2) Capsules-40,000 two-piece hard gelatine capsules for oral use, eachcontaining 250 mg. of pyridone are prepared from the followingingredients:

Gm. 3-methyl-2[lH]-pyridone 2500 Lactose, U.S.P. 1000 Starch, U.S.P. 300Talc, U.S.P. 65 Calcium stearate 25 The powdered pyridone is mixed withthe starchlactose mixture followed by the talc and calcium stearate. Thefinal mixture is then encapsulated in the usual manner. Capsulescontaining 10, 25, 50, and mg. of pyridone are also prepared bysubstituting 100, 250, 500 and 1000 gm. for 2500 gm. in the aboveformulation.

(3) Soft elastic capsules-One-piece soft elastic capsules for oral use,each containing 200 mg. of 6-methyl- 2[1H]-pyridone, are prepared in theusual manner by first dispersing the powdered active material insufiicient corn oil to render the material capsulatable.

(4) Aqueous suspension.-An aqueous suspension for oral use containing ineach 5 mL, 1 gram of pyridone is prepared from the followingingredients:

4-t-butyl-2flH1-pyridone gm 2000 Methylparaben, U.S.P. gm 7.5Propylparaben, U.S.P. gm 2.5 Saccharin sodium grn 12.5 Glycerin ml 3000Tragacanth powder gm.. 10 Orange oil flavor gm 10' F. D. and C. orangedye gm 7.5

Deionized water, q.s. to 10,000 mg.

What is claimed is:

1. A method of treating a condition exhibiting at least one of thesymptoms of pain, fever and inflammation which comprises theadministration to humans and animals of a therapeutically effectiveamount of a compound having the formula:

in which R R R and R are each hydrogen, alkyl or cycloalkyl with theproviso that at least one of the Rs is alkyl or cycloalkyl;

Z is H, alkyl, aryl, or acyl;

X is O or S;

L is hydrogen, loweralkyl, loweralkenyl, loweralkylnyl,

arloweralkyl, aryl, hydroxyloweralkyl, amino, diloweralkylamino,diloweralkylaminoloweralkyl, loweralkylaminoloweralkyl, loweralkylamino,carboxyloweralkyl, haloloweralkyl, hydroxy, loweralkoxy,loweralkylamidoloweralkyl, loweralkoxyloweralkyl, N loweralkanoylloweralkylaminoloweralkyl, N- loweralkyl-N-loweralkyl aminoloweralkyl,arloweralkenyl or heterocyclic selected from the group consisting offuryl, tetrahydropyranyl, thienyl, thiazolyl, imidazolyl, oxazolyl andpyridyl.

2. The method of claim 1 wherein the compound is of Formula I wherein atleast one R is lower alkyl or cycloloweralkyl the remaining Rs beinghydrogen; L is hydrogen, loweralkyl or aryl.

3. The method of claim 2 wherein L is hydrogen and at least one R islower alkyl, the remaining Rs being hydrogen.

4. The method of claim 3 wherein the compound is 4-methyl-2[ 1H]-thiopyridone,

3-methyl-2 1H] -thiopyridone,

S-methyl-Z 1H] -thiopyridone,

4-ethyl-2[ 1H] -thiopyridone,

4-t-butyl-2[ 1H] -thiopyridone,

5-t-butyl-2[ 1H] -thiopyridone,

6-methyl-2 1H] -thiopyridone,

3 ,4-dimethyl-2 1H] -thiopyridone,

*6-i-butyl-2 1H] -thiopyridone,

4,5-dimethyl-2[1H]-thiopyridone,

5 -t-butyl-4-methyl-2 1H] -thiopyridone,

5-n-butyl-2 1H] -thiopyridone,

5-i-propy1-2[ 1H] -thiopyridone,

6-butyl-5-methyl-2 1H] -thiopyridone,

6-pentyl-2[ 1H] -thiopyridone,

5-buty1-6-methyl-2[ 1H] -thiopyridone,

3-ethyl-4-methyl-2 1H] -thiopyridone,

5-ethyl-4-methyl-2 1H] -thiopyridone, or 5-i-propyl-6-methyl-2[ 1H]-thiopyridone.

5. The method of claim 4 wherein the compound is 4-t-butyl-2[ 1H]-thiopyridone.

6. The method of claim 4 wherein the compound is 4-ethyl-2 1H]-thiopyridone.

7. The method of claim 4 wherein the compound is 4-methyl-2 1H]-thiopyridone.

8. The method of claim 4 wherein the compound is 3,4-dimethy1-2[ 1H]-thiopyridone.

9. The method of claim 4 wherein the compound is 5-methyl-2 1H]-thiopyridone.

10. The method of claim 1 wherein the compound is of Formula II.

11. The method of claim 10 wherein the compound is4-t-butyl-2-methoxypyridine,

2-ethoxy-4-ethylpyridine,

4-methyl-2-phenoxypyridine,

4-methyl-2-methoxypyridine,

2-acetoxy4-t-butylpyridine, 4-methyl-2-propionyloxypyridine,4-methyl-2-ethoxypyridine, 3-methyl-2-methoxypyridine,4-ethyI-Z-phenoxypyridine, 4,S-dimethyI-Z-methoxypyridine,4,5,6-trimethyl-2-methoxyipyridine,4-ethyl-5'cyclopropyl-Z-ethoxypyridine, 4-t-butyl-2-methylthiopyridine,4-methyl-2-methylthiopyridine, 3-methyl-2-ethylthiopyridine,

S-t-butyl-2-phenylthiopyridine,

5-ethyl-4-methyl-2-methylthiopyridine, or

4,5,6-trimethyl-Z-methylthiopyridine.

12. The method of claim 11 wherein the compound is4-t-butyl-Z-methoxypyridine.

13. The method of claim 11 wherein the compound is4-t-butyl-Z-methylthiopyridine.

14. The method of claim '11 wherein the compound is4-methyl-2-methylthiopyridine.

15. The method of claim 11 wherein the compound is4-methyI-Z-methoxypyridine.

16. A pharmaceutical tablet or capsule comprising a pharmaceuticalcarrier and an antiinfiammatory, antipyretic and analgesic effectivenon-toxic amount within the range from about 5 milligrams to about 5grams of a compound of the formula:

10 in which R R R and R are each hydrogen, alkyl or cycloalkyl with theproviso that at least one of the Rs is alkyl or cycloalkyl;

Z is H, alkyl, aryl, or acyl;

X is O or S;

L is hydrogen, loweralkyl, loweralkenyl, loweralkynyl,

arloweral-kyl, aryl, hydroxyloweralkyl, amino, diloweralkylamino,diloweralkylaminoloweralkyl, loweralkylaminoloweralkyl, loweralkylamino,canboxyloweralkyl, haloloweralkylj hydroxy, loweralkoxy,loweralkylamidoloweralkyl, loweralkoxy-loweralkyl, N loweralkanoylloweralkyl-aminoloweralkyl, N- loweralkyl-N-loweralkyl aminoloweralkyl,arlower- *alkyl or heterocyclic selected from the group consisting offuryl, te'trahydropyranyl, rhienyl, thiazolyl, imidazolyl, oxazolyl andpyridyl.

17. The composition of claim 16 wherein the compound is of Formula Iwherein at least one R is lower alkyl or cycloloweralkyl the remainingRs being hydrogen; L is hydrogen, loweralkyl or aryl.

18. The composition of claim 17 wherein L is hydrogen and at least one Ris lower alkyl, the remaining Rs being hydrogen.

19. The composition of claim 18 wherein the compound is 4-methyl-2 1H]-thiopyridone,

3-methyl-2 1H] wthiopyridone,

5-methyl-2[ 1H] -thiopyridone,

4-ethyl-2 1H] -thiopyridone,

4-t-butyl-2 1H] -thiopyridone,

5-t-butyl-2[ 1H] -thiopyridone,

6-methyl-2 1H] -thiopyridone,

3,4-dimethyl-2[ 1H] -thiopyridone,

6-i-butyl-2 1H] -thiopyridone,

4,5-dimethyl-2[ 1H] -thiopyridone,

5-t-buty1-4-methyl-2[ 1H] -thiopyridone, 5-n-butyl-2 1H] -thiopyridone,

5-i-propyl-2 1H] -thiopyridone,

6-butyl-5-methyl-2 1H] -thiopyridone,

6-pentyl-2[l-H]-thiopy-ridone, 5-buty1-6-methyl-2[1 H]-thiopyridone,3-ethyl-4-methyl-2[11H]-thiopyridone,5-ethyl-4-methyl-2[1H]-thiopyridone, or 5-i-propyl-6-methyl-2[ 1H]-thiopyridone.

20. The composition of claim 19 wherein pound is4-t-butyl-2[1H]-thiopyridone.

21. The composition of claim 19 wherein the pound is4-ethyl-2[1H]-thiopyridone.

22. The composition of claim 19 wherein the pound is4-methyl-2[1H]-thiopyridone.

23. The composition of claim 19 wherein pound is3,4-dimethyl-2[1H]-thiopyridone.

24. The composition of claim 19 wherein pound is5-methy1-2[lHl-thiopyridone.

25. The composition of claim 16 wherein pound is of Formula II.

26. The composition of claim 25 wherein pound is4-t-butyl-2-methoxypyridine,

2-ethoxy-4-ethylpyridine, 4-methyl-2-phenoxypyridine,4-methyl-2-methoxypyridine, 2-acetoxy-4-t-butylpyridine,4-methyl-2-propionyloxypyridine, 4-methyI-Z-ethoxypyridine,3-methyl-2-methoxypyridine, 4-ethyI-Z-phenoxypyridine,4,5-dimethyl-Z-methoxypyridine, 4,5,6-trimethyl-2-methoxypyridine,4-ethyl-5-cyclopropyl-2-ethoxypyridine, 4-t-butyl-2-methylthiopyridine,4-methyl-2-methylthiopyridine, 3-methyl-2-ethylthiopyridine,5-t-butyl-2-phenylthiopyridine,

the comcomcom-

the comthe comthe comthe com- S-ethyl-4-methyl-Z-methylthiopyridine, ora r I --References Cited 27. The composition of claim 26 wherein thecom- I v 2,516,673 7/1950 Bruce 260-297 Z pound is 4 t butyl 2methoxypyrldone. l 6 Z 28'. The composition of claim 26 wherein the com-5 3,355,278 11/1967 Well at 2 0-297 pound is4-t-butyI-Z-methylthiopyridine. I

29. The composition of claim 26 wherein the com- STANLEY FRIEDMAN PnmaryExammer pound is 4-methyI-Z-methylthiopyridine. U S X R 30. Thecomposition of claim 26 wherein the compound is4-methyl-2-methoxypyridine. 260--294.8 G, 294.8 T, 296 R, 297 Z

